Alignment of elongated particles in a particle delivery device

ABSTRACT

A device for delivery of particles into biological tissue includes at least one conduit and a propellant source fluidically coupled to the conduit and configured to deliver a propellant into the conduit. A particle source is configured to release elongated particles into the conduit, the elongated particles having a width, w, a length, l&gt;w. The propellant source and the conduit are configured to propel the elongated particles in a collimated particle stream toward the biological tissue. An alignment mechanism is configured to align a longitudinal axis of the elongated particles to be substantially parallel to a direction of the particle stream in an alignment region of the conduit. The aligned elongated particles are ejected from the conduit and impact the biological tissue.

TECHNICAL FIELD

This disclosure generally involves approaches for delivering particlesinto biological tissue and to systems and methods related to suchapproaches.

BACKGROUND

Particles that can be accelerated to penetrate the skin can have a verylow active payload when a relatively light functional material, such asa drug, ink, cosmetics, etc., needs to be coated on dense, carrierparticles such as gold. Solid particles of the functional material mostefficiently carry the functional material in higher doses. However, therelatively light particle of functional material may not have enoughmomentum to be delivered into biological tissue at sufficient depth toreach target cells. Advanced gene therapies, such as DNA/RNA basedvaccines, gene based cancer tumor therapies, and genetic pharmacologyneed new delivery methods to penetrate cells.

SUMMARY

A device for delivery of particles into biological tissue includes atleast one conduit and a propellant source fluidically coupled to theconduit and configured to deliver a propellant into the conduit. Aparticle source is configured to release elongated particles into theconduit, the elongated particles having a width, w, a length, l>w. Thepropellant source and the conduit are configured to propel the elongatedparticles in a collimated particle stream toward the biological tissue.An alignment mechanism is configured to align a longitudinal axis of theelongated particles to be substantially parallel to a direction of theparticle stream in an alignment region of the conduit. The alignedelongated particles are ejected from the conduit and impact thebiological tissue.

According to some implementations, the alignment mechanism comprises anaerodynamic alignment mechanism that includes a source of sheath fluidand one more ports in the conduit configured to allow entry of thesheath fluid into the conduit in one or more sheath streams adjacent tothe particle stream. The one or more sheath streams are configured toalign the longitudinal axis of the elongated particles along thedirection of the particle stream in the alignment region.

According to some implementations the elongated particles areelectrically charged and the alignment mechanism comprises anelectrostatic alignment mechanism comprising one or more charged platesarranged proximate to the conduit.

In some implementations the elongated particles are magnetic and thealignment mechanism comprises a magnetic field generator that generatesa magnetic field within the conduit.

The elongated particles may have various features that enhancealignment, such as at least one pointed tip and/or one or more fins. Thefins can be configured to break off or fold back when the elongatedparticles penetrate the biological tissue.

In some implementations the elongated particles are solid particles of afunctional material that interacts with the biological tissue. In somecases the elongated particles include two or more types of material suchas at least a first material and a second material. The second materialmay be a functional material that interacts with the biological tissueand the first material may be a biologically inert material that hashigher density than the second material. In some implementations, thevolume of the second material in the elongated particle is greater thanthe volume of the first material. The elongated particles may comprise adrug, a cosmetic, a biologically nourishing material, or a markingmaterial.

According to some embodiments, the particle delivery device includes aparticle accelerator downstream from the alignment mechanism. Theparticle accelerator is configured to accelerate the elongated particlestoward the biological tissue.

Some implementations of the particle delivery device further include anadditional particle source configured to release additional particlesinto the particle stream. The elongated particles comprise a functionalmaterial that interacts with the biological tissue and the additionalparticles have a higher density than a density of the elongatedparticles. In some implementations, the elongated particles areelectrostatically charged and the additional particles are oppositelyelectrostatically charged from the elongated particles. Due to theiropposite charges, the elongated particles and the additional particlesform particle agglomerations as the particles are transported in theparticle stream.

Some embodiments involve a method for delivery of particles intobiological tissue. Elongated particles having a width, w, a length, l>w,and an aspect ratio, l/w, are released into a conduit and are propelledin a collimated particle stream in the conduit. The longitudinal axis ofthe elongated particles are aligned to be substantially parallel to adirection of the collimated particle stream. The aligned elongatedparticles are ejected from the conduit toward the biological tissue.Aligning the longitudinal axis of elongated particles may compriseintroducing a sheath fluid into the conduit in one or more sheathstreams adjacent to the collimated particle stream. The one or moresheath streams operate to align the longitudinal axis of the elongatedparticles to be substantially parallel to the direction of the particlestream in an alignment region.

In some implementations the elongated particles are electrically chargedand aligning the elongated particles comprises electrostaticallyaligning the elongated particles.

In other implementations the elongated particles are magnetic andaligning the elongated particles comprises magnetically aligning theelongated particles.

The aligned elongated particles may be accelerated toward the biologicaltissue using an electrostatic particle accelerator. The each of theelongated particles may comprise one or more of increased density at oneend of the elongated particle and an aerodynamic drag feature.

The method may include pre or post treating the biological tissue beforeor after ejecting the aligned elongated particles from the conduittoward the biological tissue. The pre or post treating can comprise atleast one of a laser treatment, a magnetic treatment, an electromagnetictreatment, an ultrasonic treatment and a chemical treatment.

Some embodiments involve a device for delivery of particles intobiological tissue that includes at least one conduit and a propellantsource fluidically coupled to the conduit and configured to deliver apropellant into the conduit. A particle source is configured to releaseelongated particles into the conduit, the elongated particles having awidth, w, a length, l>w. The propellant source and the conduit areconfigured to accelerate the elongated particles in a collimatedparticle stream toward the biological tissue. Acceleration of theparticles by the propellant aligns a longitudinal axis of the elongatedparticles to be substantially parallel to a direction of the particlestream. Each of the elongated particle may include at least one of afeature that provides enhanced aerodynamic drag and increased density atone end of the particle.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view, illustrating a particle delivery device inaccordance with one or more embodiments of the present disclosure;

FIG. 2 is an exploded perspective view, illustrating a particle deliverydevice in accordance with one or more embodiments of the presentdisclosure;

FIG. 3 is a section view, illustrating a particle delivery device inaccordance with one or more embodiments of the present disclosure;

FIG. 4 is a detail view, illustrating an ejector for a particle deliverydevice in accordance with one or more embodiments of the presentdisclosure;

FIG. 5 illustrates an ejector for a particle delivery device and aparticle-release tape in accordance with one or more embodiments of thepresent disclosure;

FIG. 6 shows a particle delivery device including a particle-releasetape in accordance with one or more embodiments of the presentdisclosure;

FIGS. 7A and 7B illustrate a portion of an ejector that includes afocusing mechanism configured to focus the particles into a focused beamin accordance with some embodiments;

FIGS. 8A and 8B are cross sectional views of aerodynamic particlefocusing mechanisms in accordance with some embodiments;

FIGS. 8C through 8E are cross sectional views of an electrostaticparticle focusing mechanism in accordance with some embodiments;

FIGS. 9A through 9G show exemplary configurations of two dimensional anddimensional particles comprising of a core and plurality of elongationsdistributed on the surface of the core;

FIGS. 9H through 9L show exemplary configurations for elongatedparticles of functional material in accordance with various embodiments;

FIGS. 10A through 10C show exemplary configurations for elongatedparticles comprising a combination of heavier/denser material andlighter/low-density functional material in accordance with variousembodiments;

FIGS. 11A through 11D show exemplary shapes for elongated particlesconfigured to enhance orientation control and stability according tovarious embodiments;

FIGS. 12A through 12C depict particles having a heavier/denser portionthat has increased surface area to carry a lighter/lower densityfunctional material in accordance with embodiments disclosed herein;

FIGS. 13A through 13C illustrate a portion of an ejector including analignment mechanism configure to align elongated particles in accordancewith various embodiments;

FIG. 14 is a cross sectional view of an aerodynamic particle alignmentmechanism in accordance with one or more embodiments;

FIG. 15A is a cross sectional view of an electrostatic particlealignment mechanism and particle accelerator in accordance with one ormore embodiments;

FIG. 15B is a cross sectional view of an electrostatic particlealignment mechanism in accordance with one or more embodiments;

FIG. 16A is a cross sectional view of a magnetic particle alignmentmechanism in accordance with one or more embodiments;

FIG. 16B is a cross sectional view of a portion of a particle deliverydevice that includes a particle accelerator in accordance with someembodiments;

FIG. 16C is a cross sectional view of a portion of a particle deliverydevice that includes a particle accelerator in accordance with someembodiments;

FIG. 16D is a cross sectional view of a portion of a particle deliverydevice that includes a mechanism to decelerate the focusing stream inaccordance with some embodiments;

FIG. 17 illustrates an agglomeration of charged particles in accordancewith some embodiments;

FIG. 18 is a block diagram of a particle delivery device in accordancewith various embodiments; and

FIGS. 19A through 19C are photographs comparing mechanoporation and drugdelivery using light functional particles, heavy inert particles, andboth heavy inert particles and light functional particles.

The figures are not necessarily to scale. Like numbers used in thefigures refer to like components. However, it will be understood thatthe use of a number to refer to a component in a given figure is notintended to limit the component in another figure labeled with the samenumber.

DETAILED DESCRIPTION

Embodiments described herein are directed to systems and methods fordelivering particles into biological tissue. According to the approachesdescribed herein, one or more collimating conduits are disposed within ahousing with a propellant, e.g., a pressurized gas, fluidically coupledto the one or more collimating conduits. The conduits include openingsthat allow introduction of particles into the conduit. The propellantsource and the conduits are arranged so that as the particles areintroduced, they are entrained by the gas from the propellant source andare propelled along the conduit in a particle flow stream.

As previously discussed, solid particles of functional material areneeded to efficiently carry the functional material into tissue athigher doses. However particles of functional material may not haveenough momentum to be delivered into biological tissue at sufficientdepth to reach target cells. According to some implementations discussedbelow, particles that are heavier and/or denser than the lighter/lowerdensity functional particles are ejected from the conduits, formingmicropores in the biological tissue, at least temporarily. Theheavier/denser particles may have a density greater than about 10 g/cm³,a volume greater than 0.07 μm³, and weight range of 0.5 μg to 100 mg.When penetrating the tissue, the heavier/denser particles may present anaverage cross sectional area substantially perpendicular to the tissuesurface of greater than 0.2 μm². The lighter/lower density secondparticles are ejected from the conduits, in some cases subsequently orsubstantially simultaneously with ejection of the heavier firstparticles. The heavier/denser particles may have a density more thanabout three times the density of the lighter/less dense particles. Thelighter/less dense particles may have a density less than about 10 g/cm³with diameter range of 50 nm to 1 mm. When penetrating the tissue, thelighter/lower density functional particles may present an average crosssectional area perpendicular to the tissue surface that is equal to orless than that of the heavier particles. For example, the averagepresenting cross sectional area of the lighter/lower density particlesmay be a fraction (¾, ½, ¼, etc.) of that of the heavier particles. Insome scenarios, the heavier/denser first particles penetrate thebiological tissue to create micropores that increase porosity of thebiological tissues. The lighter/less dense second particles penetratethe porous biological tissue previously formed by the first particles.If the first particles follow the second particles, the second particlesmay be driven further into the tissue. This approach allows thelighter/lower density second particles to penetrate the skin via themicropores formed by the first particles to reach target cells.

According to some implementations, the first particles and secondparticles are initially collimated in the conduit by the conduit wallsand may be subsequently focused in the conduit by a focusing mechanism.Particle collimation followed by focusing achieves enhanced spatialcorrelation between the first and second particles as they emerge fromthe device, which in turn leads to more effective delivery of functionalmaterial. Focusing occurs in a focus region of the conduits which may belocated near the conduit outlets. The first and second particles may befocused alone or together such that the largest cross sectional diameterof the focused particle stream in the focus region is less than thelargest inner cross sectional diameter of the conduit in the focusregion. In some cases, the largest cross sectional diameter of thefocused particle stream in the focus region is equal or greater than thepresenting cross sectional diameter of the first particles, wherein thepresenting cross section is the cross section of the particle that issubstantially perpendicular to the direction of the flow stream.

In some implementations, the device includes a tissue-interfacingsurface located at one end of the housing near the conduit outlets thatprovides an interface with the surface of biological tissue. Thecollimated and focused particle stream emerges from the outletsubstantially perpendicular to the biological tissue surface and canmaintain a beam diameter of less than 10 μm or equal to the presentingcross sectional diameter of the first particles over a length of about 1cm or more between the outlet of the conduit and the tissue surface. Inthe unconstrained space between the conduit outlet and the tissuesurface, the particle stream width may increase by less than about 10%of its width at the outlet.

According to some implementations, the particles, e.g., the first and/orsecond particles or other particles, are elongated particles that have awidth (w) and a length (l), wherein l>w. An alignment mechanism may beused to rotationally align the elongated particles so that the majoraxis (also referred to as the length axis) of the particles issubstantially parallel with the direction of the particle flow stream inthe conduit. The particles may have a relatively high aspect ratio,e.g., l/w is in the range of 10 to 1000 and may include features, suchas sharpened tips, fins, anisotropic weighting, structured surfaces andthe like, that enhance alignment, tissue penetration, and surface areaavailable for carrying a functional material. The particles emerge fromthe outlets of the conduits in the aligned orientation in a collimatedparticle stream and impinge on the tissue surface. According to someaspects, the aligned particles may also be focused into a narrower crosssectional area prior to ejection from the device.

Devices, methods, and systems are provided for producing high velocity,e.g., supersonic, particle streams of collimated, focused and/or alignedparticles that maintain a beam diameter less than 50 μm, or less than orequal to about 20 μm, or equal to or greater than the presenting crosssectional diameter of the first particles, less than the larger innerdiameter of conduit. In some implementations, the particle stream widthincreases by less than 10% over a length of about 1 cm or more in thespace between the outlet of the conduit and the tissue surface. When theparticles are focused in addition to being collimated, the beam diameterincrease of less than 5% may be maintained over an unconstrained 1 cmlength. The approaches described herein may reduce or eliminaterecoil/splashing, pain, and bruising associated with other needlelessinjection techniques. Such devices, methods, and systems can alsoprovide increased control and reliability of drug delivery and reducethe operational skill required to perform needleless drug injection.This, in turn, promotes more precise and accurate drug dosing.

The devices, systems, and methods described herein may be used fortargeted delivery of therapeutic, diagnostic, cosmetics, or othersubstances into or through a variety of types of tissues or biologicalbarriers, including suitable cells, tissues, or organs, including theskin or parts thereof, mucosal tissues, vascular tissues, lymphatictissues, and the like. The target cells or tissues may be in animals,mammals, humans, plants, insects, or other organisms. For example, adrug or other substance may be delivered through the stratum corneum,and into underlying dermal or epidermal tissues or cells.

According to some embodiments, a particle delivery device includes apropellant source, which may be a source that contains or produces apressurized gas. The delivery device also includes one or morecollimators, each collimator comprising one or more conduits that arefluidly connected with the fluid source. Each of the conduits isconfigured to form a collimated particle stream comprising particlesentrained in and propelled by the gas. According to some embodiments,the particle delivery device may further include a skin interfacingsurface that is adapted to mate with the skin (or other tissue surface)and align the ejector with the skin such that the plurality ofcollimated particle streams penetrate the skin in a directionsubstantially perpendicular to the skin. The skin interfacing surface isdisposed on a skin interfacing unit located downstream of the conduitoutlet. In some embodiments, described below in connection with FIG.16D, the particle delivery system may include a mechanism configured todecelerate and/or to reduce an amount of the sheath fluid as the sheathfluid approaches the skin surface. The mechanism may be part of thetissue interfacing portion of the particle delivery device and/or may belocated near the conduit outlet. For example, in some embodiments, themechanism can be located after the focused region and before interfacingwith tissue. The mechanism may redirect the propellant sheath streamfrom the high speed stream of particles such that at least a portion ofthe propellant sheath stream does not impinge on the biological tissueor impinges on the biological tissue at an oblique (non-perpendicular)angle.

The delivery device may include one or more reservoirs of functional andnon-functional material, e.g., a reservoir containing a drug in solidparticle or liquid form that is fluidically coupled to at least oneconduit of the collimators via a port between the inlet end and theoutlet end of the conduit. The port is fluidly connected (or is operableto become fluidly connected) with the reservoir, and the inlet end ofeach of the conduit is fluidly connected (or is operable to becomefluidly connected) with the gas source.

In certain embodiments, the delivery device is configured to producefocused, collimated gas streams having a sufficient velocity topenetrate human stratum corneum. For example, the delivery device may beconfigured to produce collimated gas streams having a velocity of about30 to about 1500 m/s. In certain embodiments, each of the collimated gasstreams may have a diameter of about 1 μm to about 1000 μm at a distanceof about 0.5 mm to 10 mm from the outlet of the collimator.

The collimated and focused particle stream emerges from the outletsubstantially perpendicular to the biological tissue surface and canmaintain a beam diameter of less than 10 μm or equal to the presentingcross sectional diameter of the first particles over a length of about 1cm or more between the outlet of the conduit and the tissue surface. Inthe unconstrained space between the conduit outlet and the tissuesurface, the particle stream width may increase by less than about 10%of its width at the outlet.

Effective collimation may be achieved by delivering a propellant into aconduit and controllably introducing or metering the particles into theconduit. The particles may then be introduced into the gas stream fromone or more inlet ports. The propellant may enter the channel at a highvelocity. Alternatively, the propellant may be introduced into thechannel at a high pressure, and the conduit may include a constriction(e.g., de Laval or other converging/diverging type nozzle) forconverting the high pressure of the propellant to high velocity. In sucha case, the propellant is introduced at a port located at a proximal endof the conduit (i.e., near the converging region), and the materialports are provided near the distal end of the channel (at or furtherdownstream of a region defined as the diverging region), allowing forintroduction of material into the propellant stream. It has beendemonstrated that a propellant and the material flow pattern can remainrelatively collimated for a distance of up to 10 millimeters. Forexample, the stream does not deviate by more than about 20 percent, andpreferably by not more than about 10 percent, from the width of the exitorifice for a distance of at least 4 times the exit orifice width.

In certain embodiments, the collimator may include a plurality ofconduits. Each conduit has inlet and an outlet, as shown in FIG. 4. Eachof the conduits may have a venturi, converging/diverging type nozzle,located between the inlet end and the outlet end. In certainembodiments, each conduit has an expansion neck region which expands thegas stream downstream of the venturi neck. For example, an expansionneck region may be provided at the exit of the venturi.

In some embodiments, the particle delivery device releases a particlefrom a particle source into the gas streams such that the particlesbecomes entrained in each gas stream and are transported into the skinin a direction substantially perpendicular to the skin. For example,each of the conduits may have a port that provides an opening betweenthe inlet and outlet of the conduit, that is fluidly connected with theparticle source. In certain embodiments, the port is downstream of theventuri. In some embodiments, the delivery device includes a rupturablemembrane between the particle source and the collimator. For example,the rupturable membrane may seal the port until the membrane isruptured. Rupture of the rupturable membrane may be controlled by theoperator of the device.

When the particle port is placed downstream of the venturi or downstreamof the location at which the high velocity stream of gas is established,the particles may be pushed into the high velocity gas stream by apressure differential (e.g., Bernoulli's force). For example, based onBernoulli's equation, if particles are contained in an open reservoiradjacent to a high velocity gas stream of 750 m/s, a pressure differenceof about 2.2 atm is generated and pushes the particles into the gasstream.

The delivery device may include a standoff between the collimator andthe skin interfacing surface such that a gap is provided between theoutlets of the collimator and the skin when the skin interfacing surfaceis placed against the tissue. For example, the standoff may create a gapof about 0.5 to about 10 mm between the outlets of the collimator andthe tissue surface. The standoff further allows the fluid stream to bediverted from the tissue and exhaust laterally from the stream. Theentrained particles, having much higher momentum, continue their flighttowards the tissue at substantially normal incidence.

In some embodiments, the collimator and particle source are provided inthe form of a removable cartridge. The drug delivery device may includeone or more cartridge receivers for receiving one or more removablecartridges. The cartridge may be inserted into the receiver fordelivering particles, e.g., drug particles contained in the cartridgeinto a patient's skin. The cartridge, which may be depleted of drug, maythereafter be removed and replaced. In some embodiments, the drugdelivery device includes a plurality of cartridge receivers forreceiving multiple cartridges. In certain embodiments, each cartridgemay contain an amount of a drug suitable for an individual dosage.

According to some aspects, the delivery device is configured to deliverfirst and second particles, wherein the first particles are heavierand/or have higher density than the second particles. The deliverydevice includes a collimator as discussed above and may include afocusing mechanism configured to focus the collimated particle stream toenhance the spatial correlation of the first and second particles in theparticle stream. The heavier/denser first particles are used toprecondition the tissue in a geometric pattern, such as a spot array, toenhance subsequent delivery via the lighter/lower density particle. Forexample, the heavy/denser first particles may be inert and/ordecomposable by the tissue and the lighter/lower density particles maycomprise a functional material such as a drug. The heavier/denserparticles can be accelerated through an array of microjets to generatetemporary holes in cell walls to increase permeability of cell walls todrug and/or the tissue. Lighter, lower density, solid particles can besubsequently delivered through the same array of microjets so that thelighter/lower density particles impinge the skin in the same regionswhich have enhanced permeability, enabling solid drugs and/or otherfunctional agents to be delivered intracellularly and at a specifieddepth. The diameter of the particle beam is focused to be small enoughso that there is an enhanced and high likelihood of overlap between thelanding site of the preconditioning heavier/denser particle and thelanding site of the lighter/lower density, functional particle.

In some embodiments, the particles delivered by the device may beelongated, high aspect ratio particles. The elongated particles may belighter, solid particles of a functional agent, e.g., a drug, and/or maybe heavier/denser inert particles, and/or may comprise a combinationinert heavy/dense material and lighter functional material. The deliverydevice may include an alignment mechanism configured to align elongatedparticles in the particle stream such that their length axis issubstantially parallel to the conduit axis and along the movementdirection of the particle stream.

An exemplary embodiment of a particle delivery device 10 is illustratedin FIGS. 1-3. Although the delivery device is illustrated herein as ahand held particle injector, it will be appreciated that the particledelivery device may alternatively attached to or incorporated intovarious other devices, such as catheter, a probe, needles or a surgicaldevice for example. The particle delivery device 10 includes a gassource housing 12 and a cartridge housing 14. The gas source housing 12may be dimensioned to fit comfortably in a hand when the fingers arewrapped around the cylindrical sidewall of the gas source housing 12.The particle ejector housing 14 is located at one end of the drugdelivery device 10. As illustrated in FIG. 2, the ejector housing 14 maybe located at the end of the delivery device 10 opposite a push switch16. Although the push switch 16 is illustrated at one end of thedelivery device 10, the push switch 16 can also be located elsewhere onthe device, such as on the cylindrical sidewall of the gas sourcehousing 12. The cartridge housing 14 includes at one end a tissueinterfacing surface 22. The tissue interfacing surface 22 may be agenerally planar surface that is adapted to align the collimator in asubstantially perpendicular direction to the tissue surface.

As illustrated in FIG. 3, the gas source housing 12 also surrounds a gassource 18, which contains or generates a pressurized gas. In someembodiments, the gas source 18 may be or comprise a replaceable gascontainer or cartridge that holds the gas and which can be placed withinthe gas source housing 12. The gas in the replaceable container may bepre-pressurized or may be pressurized after placement in the gas sourcehousing 12. For example, gas pressures greater than or equal to about0.2 MPa would be sufficient to entrain and drive the particles from thedelivery device. The pressurized gas may be various gases, including,but not limited to air, carbon dioxide, nitrogen, helium, or oxygen. Insome embodiments, gas is generated on-board. For example, gas may begenerated on-board by a chemical or electro-chemical reaction. Oneexample of such a system includes an electrochemical cell that breaksdown water into hydrogen gas (H₂) and oxygen gas (O₂). The water sourcecould be in liquid form or stored in a hydrogel on-board the device.Another example is a system that relies on phase transformation, such asboiling of water to generate steam. Still other examples include systemsthat utilizes a chemical reaction or decomposition, for instance, sodiumazide decomposition into sodium and nitrogen gas (N₂) or the reaction ofcalcium carbonate with an acid to yield carbon dioxide gas (CO₂). Insome embodiments, the gas is provided in a pressurized vessel and isdelivered, such as through a valve, to the collimator when needed. Forexample, the valve may be actuated by pressing a push switch on the drugdelivery device. In some embodiments, the pressure may be generated by amechanical device, such as a pump.

In the embodiment of FIG. 3, the pressurized gas is selectivelydelivered to one of three ejector cartridges 34 via a corresponding gasdelivery conduit 20. Gas delivery may be actuated by pressing the pushswitch 16. A power source 32 and a controller 33 may then selectivelyactuate a valve to control the flow of pressurized gas from the gassource 18 through the desired gas delivery conduit 20. For example, thecontroller 33 may separately simultaneously, or sequentially activateone of three control valves with each press of the push switch 16. Inembodiments in which gas is generated on-board the delivery device 10,the controller 33 may also actuate the process that generates the gas.

The ejector housing 14 in the illustrated example includes three ejectorreceivers for receiving the three ejectors 34. The ejectors 34 may beremovable and replaceable, such that the new ejectors can be insertedinto the ejector receivers once the original ejectors 34 are expended.To this end, the ejector housing 14 may comprise ejector removaldevices, e.g., spring-loaded push rods, to facilitate the removal ofexpended ejectors from the cartridge housing 14. Although slots forthree ejectors 34 are illustrated in the present embodiment, it shouldbe noted that the device could be designed to accommodate one, two,four, or any number of ejectors 34. As shown in FIG. 3, the ejectorhousing 14 includes a standoff 36 which provides a gap of distance xbetween the end of the ejectors 34 and tissue interfacing surface 22. Insome embodiments, the distance x of the gap may between about 0.1 andabout 5 mm.

The device may include a collimator for producing a plurality ofdiscrete collimated gas streams. The term “collimated” as used hereinrefers to a stream of gas which may include solid particles, e.g., firstand/or second particles as discussed above, or liquid entrained therein,that maintains a well-defined and substantially constant diameter over adesired, useful distance, including when unconstrained by a sidewallstructure. For example, the collimator may provide a stream of gas andparticles having a diameter of about 1 μm to about 1000 μm over anunconstrained distance (unconstrained by channel walls of the conduit)of about 0.5 mm to about 10 mm. The particle delivery device may beconfigured and arranged to produce gas streams having a velocity ofabout 30 to about 1500 m/s.

The collimated and focused particle stream emerges from the outletsubstantially perpendicular to the biological tissue surface and canmaintain a beam diameter of less than 10 μm or equal to the presentingcross sectional diameter of the first particles over a length of about 1cm or more between the outlet of the conduit and the tissue surface. Inthe unconstrained space between the conduit outlet and the tissuesurface, the particle stream width may increase by less than about 10%of its width at the outlet.

The first particles and the second particles may be propelled todifferent velocities. For example, the first particles maybe have ahigher velocity than the velocity of the second particles to retainfunctional material integrity of the second particles.

An exemplary ejector 34 comprising a collimator 40 is illustrated inFIG. 4. The collimator 40 includes a plurality of conduits 410, whichmay be etched, cut or milled on the surface of a plate. Although theconduits 410 are illustrated as open channels in FIG. 4, it should beappreciated that the conduits 410 are bounded by a top layer when used.The top layer may be integral with the ejector 34 or it may be a surfaceof the ejector receiver that mates with the collimator 40 when theejector 34 is received in the cartridge receiver. Each of the conduits410 has an inlet 44 at one end of the ejector 34 and an outlet 46 at theother end of the ejector 34. A venturi 48 is provided in each conduit410 between the inlet 44 and the outlet 46. Each conduit 410 includes anexpanding neck region 50 downstream of each venturi 48. As thepressurized gas passes through the venturi 48, expands into theexpanding neck region 50, and exits through outlet 46, well-defined,collimated gas streams are formed. The venturi 48 may be designed so asto produce an exit pressure of approximately 1 atmosphere such that thepressure inside the conduit is substantially equal to atmosphere, so asto not produce an expanding or contracting jet. One or more ports 52 inthe conduits 410 are provided downstream of the venturi 48 for releasingparticles from one or more sources 42 into the gas stream where theybecome engrained in the flow stream. The particles delivered by thecollimator 40 may include drug and/or non-drug particles into biologicaltissue as is described in greater detail herein.

Particles, e.g., first or second particles as discussed above, may beprovided on-board the particle delivery device from one or more particlesources. In some embodiments, the particle sources comprise one or moreparticle reservoirs. As previously described, a particle port may beprovided between each particle source and the collimator for allowingrelease of the particles therethrough into the conduits of thecollimator.

Release of the particles may be controlled by a rupturable membrane thatseals the particle port. The rupturable membrane may be ruptured by thepressure change caused by the pressurized gas being fed through thecollimator. Alternatively, the rupturable membrane may be ruptured byactuation of another element. For example, the rupturable membrane maybe ruptured by electrothermal ablation, mechanical puncturing (e.g.,with a scepter), heating (e.g., melting the membrane), chemicalreaction, or volumetric expansion of the reservoir contents.

Other release devices may be provided to control the release of theparticles from the particle reservoir. For example, an electric chargeor movable cover may be used to prevent the release of the particlethrough the drug port until such later time that release is desired andthe release device is actuated.

In some embodiments, the particles may be released from arelease-activatable tape. For example, the release-activatable tape mayhave the particles disposed on the tape. The release-activatable tapemay comprise a UV-sensitive, heat-sensitive, or electrical-sensitivematerial. The device may also include a controller that is adapted toactuate the release of the particles from the release-activatable tape.In some embodiments, the controller is adapted to actuate the release ofthe particles from the release-activatable tape after the pressurizedgas has begun to pass through the collimator.

As illustrated in FIG. 5, in some embodiments, a release-activatabletape is positioned within or adjacent to the collimator 40. Theparticle-release tape 74 may be positioned adjacent to the conduits 410downstream of the venturi 48 for releasing particles and entraining themin the gas stream. A controller 65 may selectively actuate the releaseof the particles from the particle-release tape 74.

As illustrated in FIG. 6, the particle-release tape 74 may be positionedwithin or adjacent to the conduits 78 of a collimator 62. In theillustrated embodiment, the particle-release tape 74 is situated withina relief that is etched, cut or milled in a surface of the collimatortop plate 76. As such, the particle-release tape 74 faces the conduit 78between the venturi and the outlet 72. When the particle-release tape 74is actuated to release the particles contained in the particle releasetape 74 (e.g., by the application of heat, UV, or electrical energy tothe tape), the particles are released into the conduit 78 where they areentrained in the gas flowing through the conduit 78. Additionaltechniques that can be incorporated into the particle delivery devicesand methods disclosed herein are described in U.S. Pat. Nos. 6,328,436,7,188,934, and 8,550,604 which are incorporated herein by reference.

The delivery device may be configured to deliver various types ofparticles and may also deliver liquids, in the form of a stream ordroplets. For example, the particles delivered may be or compriseheavier/denser particles that are configured to form micropores in thebiological tissue; the particles delivered may be or comprise abrasiveparticles configured to abrade the biological tissue; the particlesdelivered may be or comprise lighter weight particles such as solidparticles of functional material configured to interact with thebiological tissue in some therapeutic or non-therapeutic way. Thefunctional material may comprise drugs, cosmetics, nutritional ornourishing substances, tissue marking substances and/or any other typesof particles. These categories of particles are not mutually exclusiveand may overlap, for example, according to some implementations, thelighter weight particles may also be abrasive or the heavier/denserparticles may include a coating of the functional material.

As used herein, the term “drug” refers to any chemical or biologicalmaterial or compound suitable for administration by the methodspreviously known in the art and/or by the methods taught in the presentdisclosure, that induces a desired biological or pharmacological effect,which may include but is not limited to (1) having a prophylactic effecton the organism and preventing an undesired biological effect such aspreventing an infection, (2) alleviating a condition caused by adisease, for example, alleviating pain or inflammation caused as aresult of disease, and/or (3) either alleviating, reducing, orcompletely eliminating the disease from the organism. The effect may belocal, such as providing for a local anesthetic effect, or it may besystemic. The drug may be a therapeutic, prophylactic, antiangiogenicagent. For example, the drug may be a vaccine. The drug may beformulated in a substantially pure form or with one or more excipientsknown in the art. The excipient material may be homogenously mixed withthe drug or heterogenously combined with the drug. For example, the drugmay be dispersed in an excipient (matrix) material known in the art, ormay be included in a core or coating layer in a multi-layered structurewith an excipient material. In some embodiments, the excipient materialmay function to control in vivo release of the drug, for example toprovide timed release (e.g., controlled or sustained release) of thedrug. In some embodiments, particles may include biodegradable materialthat is used as a sacrificial layer/coating on the functional materialand potentially for protecting the active material during jetting andpenetration. In some embodiments, the biodegradable material may be aconstituent for controlling the release of drug content. Theheavier/denser particles may comprise biodegradable and/or dissolvableparticles that are absorbed by biological tissue. Where biodegradablematerials are used for the heavier particles, these approaches canreduce foreign material residence in the tissue.

Some embodiments involve the use of tissue abrasive particles inaddition to the heavier/denser particles and lighter/less denseparticles previously discussed. The tissue abrasive particles aresuitable for abrading the surface of a biological tissue after deliveryfrom the device and impinging the biological tissue. According to someaspects the tissue abrasive particles may be made of aluminum oxide.

The heavier/denser particles may be made of a material having densitygreater than 10 g/cm³ and may comprise a metal such as gold, platinum orsilver. The heavier/denser particles may have a shape, e.g., pointedtip, wedge shape, etc. that enhances penetrating the tissue to apredetermined depth. The heavier/denser particles are particularlyeffective at creating micropores in tissue.

The device may also contain and deliver nourishing or nutritionalparticles. The nourishing or nutritional particles may be any particlessuitable for promoting or maintaining the viability of the cells of thebiological tissue. Such particles may include vitamins, minerals, andother non-drug particles that contain nutrients.

The device may also contain and deliver cosmetic particles. The cosmeticparticles may be any particles suitable for providing a cosmetic effectto the biological tissue when delivered to the tissue. For example, theparticles may be particles that diminish the appearance of wrinkles,that provide color, such as for tattoos, or alter the coloration of thebiological tissue, or that create or reduce localized swelling.

The device may also contain and deliver tissue marking particles. Thetissue marking particles may be any particles suitable for marking atissue for identification, whether such an identification may be madevisually, with or without the assistance of technology (e.g., an imagingtechnology). For example, the particles may comprise an ink or dye orthe particles may contain an agent that is visible or capable of imagingwith an imaging technology, such as X-Ray, infrared (IR), magneticresonance imaging (MRI), computed tomography (CT), or ultrasound.

In certain embodiments, the particles have a volume average diameter ofabout 0.1 to about 250 microns. In some embodiments, the particles havean average diameter equal to or less than ⅕ the width of the conduit orchannel, and even more preferably equal to or less than 1/10 the of thewidth of the conduit or channel.

In some embodiments, the ejector may be configured to both collimate theparticles entrained in the gas flow stream and to focus the particles.The ejector may include a focusing mechanism configured to focus theparticles into a cross sectional area wherein the largest diameter ofthe cross sectional area is a fraction of the largest inner diameter ofthe conduit. In some implementations, the cross sectional area of thefocused stream is less than 1/10, less than 1/100, or less than 1/1000of the inner diameter of the conduit after focusing. In some cases, thefocused, collimated stream of particles can more effectively deliver thefunctional material to the tissue due to spatial correlation between thefirst particles (heavier/denser particles) and the second particles(lighter particles of functional material). For example, the device canbe configured to collimate and focus the stream of first and secondparticles to provide a specified spatial correlation of the particles atthe impact site on the tissue. In some embodiments, the impact site ofthe particles has a diameter equal to or greater than the presentingcross sectional diameter of the first particles. In some embodiments,the impact site of the second particles has a diameter less than about0.5 times the diameter of the impact site of the first particles.

When both first and second particles are ejected by the device,increased spatial correlation of these particles increases theprobability that a lighter weight particle will follow a heavier weightparticle into a micropore created by the heavier weight particle or thata lighter weight will be driven into the tissue by a heavier weightparticle that impacts the tissue after the lighter weight particle,thereby propelling the lighter weight particle through a micropore tosuitable depth in the tissue. Note that the terms “first” and “second”are used herein to identify different types of particles and are notmeant to convey any particular order. The first particles may bedelivered before, after, or during the time that the second particlesare delivered.

FIG. 7A illustrates a portion of an ejector 80 including conduits 710that form well-defined collimated streams of particles entrained in acarrier gas 88. The ejector 80 includes a focusing mechanism 795, e.g.,an aerodynamic and/or electrostatic focusing mechanism, configured tofocus the particles into a focused beam. A particle electrostaticaccelerator 796 may optionally be used in conjunction with a particlealignment and/or particle focusing mechanism.

The particles emerge from the outlets 86 of the conduits 82 in analigned and focused beam substantially perpendicular to the tissuesurface. The ejector includes a tissue interfacing surface 90 configuredto be placed on skin or other tissue. When the tissue interfacingsurface 90 is placed on the skin 92, the outlets 86 are at a distance xabove the surface 92. When the particles impact the skin surface 92,they may form micropores 94 in the skin.

The inset FIG. 7B shows the focused particle beam downstream of thefocusing mechanism. The particle beam is focused into a cross sectionalarea having width d₂ which is a fraction, e.g., less than 1/10, lessthan 1/100, or less than 1/1000 of the conduit inner diameter width d₁in the focus region.

As illustrated in FIG. 8A, an aerodynamic focusing mechanism 895 maycomprise at least one source 810 of sheath fluid 811 and at least onesheath fluid port 820 that allows the sheath fluid 811 to enter theconduit 83 a to form at least one sheath flow stream 850 that focusesthe collimated particle stream 860. In some cases, the sheath fluid maycomprise the propellant used to form the collimated particle stream. Insome cases, the sheath fluid may be a different from the propellant, maybe or include a liquid drug, may include additional particles and/or maybe a mixture of the propellant other liquid or particles. FIG. 8Aillustrates the scenario wherein upstream of the focusing mechanism theconduit 83 a is relatively wider and the particles are initiallydispersed in the conduit. In the focus region, the sheath fluid 850pinches the particles stream 860 in and downstream of the focus regioninto a particle stream 861 having a narrower cross sectional area. Thelargest cross sectional width of the focused particle stream is afraction of the width of the internal diameter of the conduit in thefocus region.

FIG. 8A illustrates a particle reservoir 875 configured to deliver theparticles inline with the conduit 83 a. The sheath 850 focuses thepayload from a diameter D into a microjet of diameter d and acceleratesthe payload in the focus region while avoiding increases in the shear onthe particle payload The flow streams in array of parallel entrainmentmicrojet conduits and propellant gas (e.g., air, helium, etc.) may reachover 300 m/sec for 1 atm pressure input used. Much higher velocities arepossible using this approach, e.g. velocities in excess of 300 m/s.Higher pressure can be used to achieve higher velocities.

FIG. 8B illustrates the scenario wherein the conduit 82 a is initiallyrelatively narrow before the sheath fluid 811 is introduced. In thefocus region, the sheath fluid 811 maintains the particle stream 860 towithin a narrow cross section of the wider conduit 82 b. The width ofthe particle stream can be actively changed/controlled by adjusting theflow rate of the gas sheath flow.

FIGS. 8C through 8E show side and end cross sectional views of anelectrostatic particle focusing mechanism 97 comprising at least onecharged plate 871 having a length, L_(cp), and width, W_(cp), that isless that the width of the conduit in the focus region and about equalto the desired focused particle beam. Particles 880 can be charged byionization, ion bombardment, tribocharging, or other means. Particles880 having a charge opposite the charge on the charged plate 871 areelectrostatically attracted and move toward the center of the conduit 82into a focused particle stream 881. When charged particles 880 are used,the ejector may also include an electrostatic particle accelerator asshown in FIG. 8C. The charged particles 880 are first attracted andaccelerated toward the oppositely charged plate 871 and, afteraccelerating past the oppositely charged plate 871, are repelled by aplate 872 having the same charge as the particles 880, thus acceleratingthe particles 880 toward the tissue surface 92. The electrostaticfocusing and/or acceleration may be used in conjunction with aerodynamicfocusing using sheath fluid previously discussed.

The particles delivered by the delivery device may have a variety of twodimensional and three dimensional shapes comprising lighter, functionalmaterial, e.g., drug material, and heavier/denser material, e.g.,mechanoporation material. In some implementations, portions of theparticles may be the lighter material and other portions may be theheavier denser material. For example, the particles may be circular orspherical as previously shown and in general have any two dimensional orthree dimensional shape. Illustrative particle shapes include a starshape with any number of points, as shown in FIGS. 9A through 9F and athree dimensional star shown in FIG. 9G. The particles of FIGS. 9Athrough 9G may be made partially of functional material and partially ofheavier denser material. In some implementations, the center or coreportion of the particles may be or comprise the lighter, functionalmaterial and the elongations extending from the core may be or comprisethe heavier, denser material.

According to some implementations at least some of the particlesdelivered by the delivery device are elongated particles, e.g., havingan aspect ratio greater than about 5, or in a range of about 5 to about50, for example. The length of the elongated particles may be in therange of about 1 μm to about 1000 μm, or in a range of about 10 μm toabout 100 μm. The width of the elongated particles may be in the rangeof about 0.25 μm to about 100 μm, or about 2 μm to about 50 μm. In someimplementations, the length and/or width of the particles may be greaterthan 100 μm. As discussed above, a focused, collimated particle streammay be used to enable tight spatial correlation between high densitymechanoporation particles and low density drug particles. Thecorrelation should allow a drug or other functional material to diffuseinto cells before the membrane has reclosed. The use of elongatedparticles may be employed to further facilitate correlated delivery ofheavier mechanoporation particles and lighter particles of a functionalmaterial, e.g. drug particles. A high aspect ratio and alignment ofparticles normal to skin surface can allow sufficiently high momentumand sufficiently small cross section for adequate penetration of drugmaterial. The high aspect ratio scales the ratio of mass to impact crosssectional area in a beneficial manner relative to spherical form factorand enhances penetration through reduced drag.

According to some implementations, the elongated particles comprise highaspect ratio solid rods of a lighter weight, functional material, e.g.,drug material, as shown in FIGS. 9H-9L. FIG. 9H shows a rod-shaped solidfunctional particle 910 having a high aspect ratio. FIG. 9I shows aparticle 920 that is similar to that of FIG. 9H, but includesintentionally tapered ends 921 to enhance tissue penetration.

Elongated objects will align parallel to the stream lines in the conduitwith maximum drag end downstream as they are accelerated by the fastermoving fluid. However, because of the small drag forces in gas, thealignment time is fairly long (e.g., on the order of tens of seconds forparticles in the 1 to 10 μm size range). In some configurations, evenafter the particles are aligned in the gas stream, small perturbationscan misalign the objects again. One way to speed up the alignment and tostabilize the orientation of the particles is to add fins at one end ofthe elongated particles. These fins increase the drag at one end, whichincreases the rate of rotation into the aligned position, whilestabilizing the dart against misalignments due to perturbations. Asshown in FIGS. 9J and 9K, the elongated particles 930, 940 are shownwith two possible implementations of the fins 931, 941. Fin 931comprises a widened end section at one end of particle 930. Fin 941comprises ridges at one end of particle 940. However, in some cases,protrusions can be detrimental to skin penetration. FIG. 9L illustratesfins 951 that can be broken off easily as the particle 950 enters theskin or are flimsy enough to fold back. Brush structures occur in theextracellular matrix and are easily endocytosed.

In some implementations, the elongated particles are combinationparticles that include a combination of materials, such as dualmaterial, high aspect ratio structures that include a denser/heaviermaterial in one or more regions and include a less dense, lighterweight, functional material in one or more relatively long regions offunctional material.

FIGS. 10A through 10C show dual material particles 1010, 1020, 1030,e.g., comprising a high density penetration enhancer material and lowdensity drug material). FIG. 10A shows a high density particle ormaterial portion 1011 bonded to a relatively long functional particle ormaterial portion 1012. For stiff formulations of the functional materialit should not matter which end impacts the skin first because it is themomentum and cross section which determine the penetration depth.

The use of high aspect ratio particles increases the likelihood thatparticles are aligned such that they are substantially perpendicular tothe tissue upon impact. One or both ends of the combination particlecould be tapered to further enhance penetration, as illustrated byparticle 1020 of FIG. 10B which includes a tapered heavier/denserportion 1021 on one end and a tapered functional portion 1022 on theopposing end of the high aspect ratio particle. The particle 1030 shownin FIG. 10C illustrates that multiple regions of various types ofmaterials (e.g., heavier/denser material 1031 and lighter material 1032)can be aggregated in a linear particle configuration to adjust the totalmass needed for optimal penetration and/or alignment stability. As shownin FIG. 10C, the higher weight portions 1031 of a particle (and higherweight particles in general) can have high aspect ratio shapes.

Shaping the particles can be beneficial for orientation control andstability. A few examples of shaped particles are illustrated in FIGS.11A through 11D although it will be appreciated that there are a greatnumber of shapes that could be used. FIGS. 11A through 11D provide anexemplary, non-limiting set of shapes, including a combination materialparticle 1110 comprising a heavier material 1111 and a lighter material1112 arranged in an approximately triangular shape (FIG. 11A); a blunttapered combination particle 1120 comprising a heavier material 1121 anda lighter material 1122 (FIG. 11B); a pointed taper combination particle1130 comprising a heavier material 1131 and a lighter material 1132(FIG. 11C); and a tear drop shaped combination particle 1140 (acombination of the blunt taper and pointed shapes) comprising a heaviermaterial 1141 and a lighter material 1142.

For combination particles, the particle may be formed in shapes thatincrease the surface area of a heavier material that is available tocarry the functional material. For example, an increase in surface areacan be achieved by using a higher density material 1211 formed in ahollow shape, e.g., a hollow cylinder, as shown in the cross section(FIG. 12A) and perspective (FIG. 12B) views of particle 1210. Thefunctional material 1212 is disposed in and on the hollow cylinder ofheavier/denser material 1211.

As another example, the surface of the heavier/denser material can bestructured to include fins (shown in FIG. 12C) or other structuredshapes (ridges, pyramids, hemispheres, etc.) that increase the surfacearea available to carry the functional material. The structured surfacecan be an inner surface, e.g., inner surface of a cylinder, an outersurface, or both the inner and outer surfaces can be structured toincrease surface area. The combination particles having one or morestructured surfaces may be elongated or non-elongated, e.g. a sphericalparticle of the heavier/denser material can have a structured surface.

The elongated particles discussed above may be used with or withoutfocusing, however, focusing as discussed herein is particularly usefulto constrain the heavier mechanoporation particles and lighterfunctional particles, e.g., drug particles, more tightly to increasespatial correlation significantly. In implementations that use separateheavy and light particles, either the heavy particles, the lightparticles, or both may be elongated.

Some embodiments involve a particle delivery device comprising a broadarea ejector, such as an ejector having a few larger conduits or asingle larger conduit. In some examples, the few conduits or singleconduit may have an inner diameter of about 1 cm. Such a broad areaejector may be configured to deliver aligned elongated particles, suchas the particles illustrated in FIGS. 9H through 9L with or withoutfocusing. For example, in both broad area and narrow area particleejectors, high aspect ratio particles having enhanced aerodynamic dragat the front end and/or having a higher density tail end may be alignedduring acceleration of the particles as the air is flowing significantlyfaster than the high aspect ratio particles.

FIG. 13A illustrates a portion of an ejector 1380 including conduits1310 that form well-defined collimated streams of elongated particles1395 entrained in a carrier gas 1388. The ejector 1380 includes analignment mechanism 1395, e.g., an aerodynamic, electrostatic, and/ormagnetic alignment mechanism, configured to align the elongatedparticles 1395 so that the longitudinal dimension of the elongatedparticles is aligned with the flow direction of the gas and particlestream. For example, the elongated particles may be aligned such thatthe length axis of the particle makes an angle less than about 20degrees with the flow direction 1399. A particle electrostaticaccelerator 1396 may optionally be used in conjunction with the particlealignment mechanism. The ejector may also include a particle focusingmechanism in some implementations.

As shown in inset FIG. 13B, upstream from the particle alignmentmechanism 1395, the elongated particles 1395 may be non-aligned withrespect to the direction of flow 1399. Non-aligned means that the lengthaxes of most of the particles are oriented at angles greater than ±20degrees with respect to the flow direction.

After the particles interact with the alignment mechanism 1395, theelongated particles 1395 are substantially aligned, e.g., the lengthaxis of a substantial majority (greater than 75%) the particles makes anangle of less than about ±20 degrees or even ±5 degrees with respect tothe flow direction 1399 as illustrated in the inset FIG. 13C. The twomechanisms of alignment due to differential shearing and torque due tomass distribution during acceleration may tend to align ends with higherdrag and lower mass toward tissue end of flow.

The ejector 1380 includes a tissue interfacing surface 1390 configuredto be placed on skin or other tissue 1392. When the tissue interfacingsurface 1390 is placed on or near the skin 1392, the conduit outlets1386 are at a distance x (see FIG. 13A) above the surface 1392. In someimplementations, the tissue interfacing surface 1390 may be a componentof a structure, such as a hollow flexible tube. When the particles 1395impact the skin surface 1392, they form micropores 1394 in the skin andthe carrier gas 1388 travels substantially parallel to the skin 1392.

As illustrated in FIG. 14, an aerodynamic alignment mechanism 1495 maycomprise, for example, at least one source 1410 of sheath fluid 1411 andat least one sheath fluid port 1420 that allows the sheath fluid 1411 toenter the conduit 1482 to form at least one sheath flow stream 1450 thataligns the elongated particles 1488 in the collimated particle stream1460. As shown in FIG. 14, before interaction with the sheath fluid1411, the particles 1488 are less aligned than the particles 1488downstream in the alignment region. The sheath fluid may comprise thepropellant used to form the collimated particle stream. In some cases,the sheath fluid may be a different from the propellant, and may be orinclude a liquid drug, a gas, and/or a liquid or gas that containsadditional solid particles. As illustrated by the example of FIG. 14, astream of propellant gas and particles several microns in diameter canbe injected into a laminar sheath flow of air. The particle ejector maybe designed to reduce turbulence which can be accomplished for lowReynolds numbers at such small scales. Diffusion between the propellantand sheath flows is negligible in the time from ejection into the sheathand impact with the tissue. Thus lateral spatial correlation can beenhanced in rough proportion to the ratio of the diameter of the fullconduit and the carrier stream. Arbitrary loading of first(heavier/denser) material and the drug or other functional material canbe chosen to provide sufficient drug delivery.

FIG. 15A shows an electrostatic particle alignment mechanism 1597comprising one or more charged plates 1571, 1572 disposed proximate tothe conduit 1570. As illustrated in FIG. 15, the electrostaticallycharged plates 1571 1572 comprise a positively charged plate 1571 and anegatively charged plate 1572 spaced apart from one another and wrappedaround the conduit 1570. Particles 1580 moving along direction 1599 arepositively charged at one end causing the charged end to be repelledfrom and rotate away from the positively charged plate 1571 and to beattracted to and rotate toward the negatively charged plate 1572 thuscausing rotational alignment of the particles 1580 in the conduit 1570.

When charged particles 1580 are delivered, charged plates 1571, 1572,1573 may be used as an electrostatic particle accelerator. The chargedparticles 1580 are first repelled by plate 1571 and are acceleratedtoward the oppositely charged plate 1572. After accelerating past theoppositely charged plate 1572, the positively charged particles 1580 arerepelled by a plate 1573 which has the same charge as the particles,thus accelerating the particles 1580 toward the tissue surface. Withcharge at only one end of the high aspect ratio particles electricfields can be used to retard one end and effectively enhance theaerodynamic alignment effectiveness of the air which is moving at ahigher speed than the particles.

Another configuration of an alignment mechanism 1598 is shown in FIG.15B. Particles 1581 are oppositely charged at either end forming adipole and are entrained in the gas propellant 1520 as they move throughconduit 1531 along direction 1599. The charged plates 1575, 1576 createan axial field which provides an aligning torque to the dipolarparticles.

FIG. 16A illustrates a magnetic alignment mechanism for a particledelivery device. Magnetic, elongated particles 1680 move through theconduit 1620 generally along direction 1699. A solenoid 1601 is coaxialwith the conduit 1620 and generates a magnetic field having direction1698. The magnetic field operates on magnetic particles 1680 causingmagnetic particles 1680 to align with the field.

In some embodiments, a magnetic field gradient is used to focus theparticles and to accelerate the magnetic particles toward the tissue Themagnetic particle focusing and acceleration mechanism may be used, forexample, in conjunction with the magnetic particle alignment mechanismof FIG. 16A and/or may be used with any of the particle focusingapproaches disclosed herein. As shown in FIG. 16B, the particle focusaccelerator 1619 may comprise a planar electromagnetic coil 1650 locatednear the tissue 1621. When activated, the planar coil 1650 generates agradient magnetic field that focuses and accelerates magnetic particles1660 moving in the channel 1640 toward the tissue 1621. The diameter ofthe planar coil 1650 controls the focusing of the particle stream andthe strength of the magnetic field, which is controlled by the currentthrough the coil 1650, controls the particle acceleration.

FIG. 16C illustrates a magnetic particle accelerator comprising amagnetic field source 1675, such as the planar coil previously discussedlocated downstream from the particle focusing mechanism shown in FIG.8A. The magnetic field source 1675 creates a gradient magnetic fieldthat accelerates magnetic particles toward the tissue. According to someimplementations, the first particles may be accelerated, e.g.,electrostatically or magnetically, accelerated whereas the secondparticles are not electrostatically or magnetically accelerated causingthe first particles to attain a higher velocity than the velocity of thesecond particles.

In some configurations it can be helpful to remove and/or decelerate atleast some of the propellant in the high speed stream of particles justbefore or just after the focused particle stream is unconstrained by thechannel. FIG. 16D illustrates a propellant deceleration mechanism 1665located near the outlet 1661 a of the conduit 1661 near tissue 1666. Thedeceleration mechanism includes channels 1665 a, 1665 b that remove someof the propellant and allow the focused particle stream 1667 to continueto proceed toward the conduit outlet 1661 a. In some implementations,the channels 1665 a, b may be coupled to a vacuum source.Deceleration/redirection of the propellant serves to reduce splash backof the propellant and particles and/or reduces the damage to the tissue.

In some implementations, charged particles can be used to increasespatial correlation of heavier/denser particles and lighter functionalparticles as shown in FIG. 17. the first particles 1710 (heavier/denserparticles) are charged and the second particles 1720 (functional lighterparticles) are oppositely charged. The first particles 1720 are repelledby each other as are the second particles 1710. However, the first andsecond particles 1710, 1720 are attracted to each other. The attractionbetween the first and second particles 1710, 1720 enhances spatialcorrelation of the first and second particles as particles of oppositecharge sign form particle agglomerations 1701 as depicted in FIG. 17.Agglomerating particles in this way may also serve to enhancepenetration of the particles into the tissue.

In some embodiments, the delivery device is capable of delivering atreatment to the tissue before and/or after delivery of the particlesthat enhances absorption of the functional material. For example, insome implementations, the pretreatment may involve bombarding the tissuewith abrasive particles, delivering a liquid drug or other liquid to thetissue, forming micropores in and/or abrading the tissue surface using alaser, applying electromagnetic pulses to the tissue.

FIG. 18 is a block diagram of a particle delivery device 1800 inaccordance with some configurations discussed herein. The particledelivery device 1800 includes one or more ejectors comprising conduits,a propellant source fluidically coupled to the conduits, and sources forfirst and second particles, each source coupled to openings in theconduit walls for introduction of the first and/or second particles intothe conduits. One or both of the first and second particles may beelongated, charged and/or magnetized particles. Each ejector includes atleast one conduit into which the propellant is released, forming gasstreams that entrain the first (heavier/denser) particles and/or second(lighter, functional) particles as they are introduced into theconduits. The ejectors are configured to collimate, focus, align, and/oraccelerate the first and/or second particles as the particles movethrough the conduits. Optionally, the delivery device 1800 includes oneor more pre or post treatment substance or apparatus. Optionally, thedelivery device 1800 includes a unit or structure for redirecting thesheath gas at the conduit outlet leaving the particles traveling at highspeed to impinge on the tissue. The pre or post treatment substance maycomprise a particle, a liquid, or a gas. The pre/post treatmentparticle/liquid/gas may be delivered to the tissue through the conduits,with the pre/post treatment substance entering the conduits throughopenings in the conduit walls.

In some implementations, the pre/post treatment apparatus is an energysource that delivers energy to the tissue. In various implementations,the energy source may provide optical energy, high frequencyelectromagnetic energy, and/or ultrasonic energy, for example.

In one implementation, the pre/post treatment apparatus comprises anedge emitting semiconductor laser arranged such that the laser lightgenerated by the laser (or array of lasers) travels through and isguided in each conduit to the tissue surface. The laser light may abradethe tissue surface before and/or after delivery of the first and/orsecond particles in some cases. In a higher power implementation, thelaser light may have sufficient energy to produce micropores in thetissue to a depth suitable for delivering the functional substance,e.g., at a depth range of about 1 μm to about 1 mm. A lens or otherfocusing element may be located at the output end of the delivery deviceto provide for focusing the laser light into a high power spot on theskin to provide microporation.

In some implementations, the pre/post treatment apparatus may comprise agenerator configured to produce magnetic pulses that enhanceskin/mucosal surface permeation and provide for enhanced absorption ofthe functional material (dermaporation for skin delivery). For example,the generator can be configured to generate magnetic fields having apeak magnetic field of 5 mT, pulse duration of 400 μs, and duty cycle of5% or an average magnetic field of 0.25 mT or more.

In some implementations, the pre/post treatment apparatus may comprise agenerator configured to produce electrical pulses that provideelectroporation for enhanced absorption of the functional material. Forexample, the generator can be configured to apply 50 V transdermally in200 ms pulses or 100 V in 1 ms pulses. In some implementations, thepre/post treatment apparatus may comprise an ultrasonic generatorconfigured to generate ultrasonic waves that increase the permeabilityof tissue.

Some embodiments discussed herein provide for physical tissue permeationenhancement to enable uptake of solid drug powder or other functionalsubstances. These techniques increase cell wall permeation forsubsequent payload penetration, through mechanoporation via particles. Adelivery device discussed herein uses multiple conduits that can providean array of precision spot target zones and enables multiparticledelivery schemes. In some implementations, all the conduits are used toeject particles and in other implementations fewer than all of theconduits are used to eject the particles. For example, the conduits ofthe delivery device may be sourced with particles or not in a gray scalemanner to create patterned implantation of functional particles.Heavy/dense inert particles can be jetted into the tissue, formingtransient diffusion pathways and enhancing cell wall permeability in amechanoporation step that occurs before, simultaneous with or afterdelivery of the functional material to the tissue. The highly loaded,lighter mass drug particulates can be jetted to reach the target spotfor internalization by cells. The approaches discussed herein mayutilize micro electrical mechanical systems (MEMS) arrayed channels thatprovide confined jet streams and high probabilities for target overlapfor the two types of particles. An in-line parallel device designconfines particles to a few streamlines (to less than a few particlediameters in width) in the center of the conduit thus creating highprobabilities for particles being well aligned, spatially correlatedwith one another. This width can be maintained when the particle streamis unconstrained by the conduit walls and reaches the tissue surface aspreviously discussed.

To realize drug internalization by cells, the drug should beinterstitially transported to the mechanoporated regions. Since thisarchitecture provides micro-scale spatial precision to accurately landthe drug particles in <10-20 μm proximity to the mechanoporated cells,the diffusion time for interstitial transport of pDNA (<400 s;considering the interstitial diffusion coefficient, D, is ˜10⁻⁸ to5×10⁻⁹ cm²/s) scales with the duration of the cell wall recovery times(˜9 min for pore resealing using other methods).

In some scenarios, cell wall recovery times can be very slow compared tothe particle arrival frequency and therefore, the light solid particlesarrival times to the target site and transport times into the cell canbe faster than cell wall recovery times and thus pDNA will be able tointernalize by cells. The approaches discussed herein can enablesignificantly higher doses and efficiencies than technologies that arerestricted to low concentration coated payloads for intracellulardelivery (low density solid drug particles delivered by these devices donot penetrate deep and do not enter cells). The individual deliveryspots on the tissue can be smaller (e.g., less than 50 μm) and massivelyarrayed with low cost MEMS fabrication. In some cases plastic injectionmolding can be used for high volume manufacturing.

FIGS. 19A through 19C show experimentally observed penetrationenhancement of a drug in a gel that simulates biological tissue. Thelighter particles when used alone have good drug loading but show poorpenetration as shown in FIG. 19A. The heavy/dense particles when usedalone have good penetration but poor drug loading as shown in FIG. 19B.FIG. 19C shows the results for heavy particles followed by lightparticles. This technique exhibits almost 10× deeper penetration oflighter functional particles than when the lighter particles are usedalone.

The foregoing description of various embodiments has been presented forthe purposes of illustration and description and not limitation. Theembodiments disclosed are not intended to be exhaustive or to limit thepossible implementations to the embodiments disclosed. Manymodifications and variations are possible in light of the aboveteaching.

The invention claimed is:
 1. A device for delivery of particles intobiological tissue comprising: at least one conduit; a propellant sourcefluidically coupled to the conduit and configured to deliver apropellant into the conduit; a particle source configured to releaseelectrostatically charged elongated particles into the conduit, theelongated particles having a width, w, a length, l>w, the propellantsource and the conduit configured to propel the elongated particles in acollimated particle stream toward the biological tissue; anelectrostatic alignment mechanism comprising one or more charged platesarranged proximate to the conduit, the electrostatic alignment mechanismconfigured to align a longitudinal axis of the elongated particles to besubstantially parallel to a direction of the particle stream in analignment region of the conduit, wherein the aligned elongated particlesare ejected from the conduit and impact the biological tissue.
 2. Thedevice of claim 1, wherein the alignment mechanism comprises anaerodynamic alignment mechanism that includes: a source of sheath fluid;and one more ports in the conduit configured to allow entry of thesheath fluid into the conduit in one or more sheath streams adjacent tothe particle stream, the one or more sheath streams configured to alignthe longitudinal axis of the elongated particles along the direction ofthe particle stream in the alignment region.
 3. The device of claim 1,wherein: the elongated particles are magnetic; and the alignmentmechanism comprises a magnetic field generator that generates a magneticfield within the conduit.
 4. The device of claim 1, wherein theelongated particles have at least one pointed tip.
 5. The device ofclaim 1, wherein the elongated particles have one or more fins.
 6. Thedevice of claim 5, wherein the fins are configured to break off or foldback when the elongated particles penetrate the biological tissue. 7.The device of claim 1, wherein the elongated particles are solidparticles of a functional material that interacts with the biologicaltissue.
 8. The device of claim 1, wherein the elongated particlesinclude at least a first material and a second material, wherein thesecond material is a functional material that interacts with thebiological tissue and the first material is a biologically inertmaterial that has higher density than the second material.
 9. The deviceof claim 8, wherein a volume of the second material is greater than avolume of the first material.
 10. The device of claim 1, furthercomprising a particle accelerator downstream from the alignmentmechanism, the particle accelerator configured to accelerate theelongated particles toward the biological tissue.
 11. The device ofclaim 1, wherein the elongated particles comprise a drug, a cosmetic, abiologically nourishing material, or a marking material.
 12. The deviceof claim 1, further comprising an additional particle source configuredto release additional particles into the particle stream, wherein theelongated particles comprise a functional material that interacts withthe biological tissue and the additional particles have a higher densitythan a density of the elongated particles.
 13. The device of claim 12,wherein: the elongated particles are electrostatically charged; theadditional particles are oppositely electrostatically charged; and theelongated particles and the additional particles form particleagglomerations as the particles are transported in the particle stream.14. A method for delivery of particles into biological tissuecomprising: releasing electrostatically charged elongated particles intoa conduit; propelling the elongated particles in a collimated particlestream in the conduit, the elongated particles having a width, w, alength, l>w, and an aspect ratio, l/w; electrostatically aligning alongitudinal axis of the elongated particles to be substantiallyparallel to a direction of the collimated particle stream; and ejectingthe aligned elongated particles from the conduit toward the biologicaltissue.
 15. The method of claim 14, wherein aligning the longitudinalaxis of elongated particles comprises introducing a sheath fluid intothe conduit in one or more sheath streams adjacent to the collimatedparticle stream, the one or more sheath streams operating to align thelongitudinal axis of the elongated particles to be substantiallyparallel to the direction of the particle stream in an alignment region.16. The method of claim 14, wherein: the elongated particles aremagnetic; and aligning the elongated particles comprises magneticallyaligning the elongated particles.
 17. The method of claim 14, furthercomprising accelerating the aligned elongated particles in the particlesstream toward the biological tissue using an electrostatic particleaccelerator.
 18. The method of claim 14, wherein each of the elongatedparticles comprises one or more of increased density at one end of theelongated particle and an aerodynamic drag feature.
 19. The method ofclaim 14, further comprising pre or post treating the biological tissuebefore or after ejecting the aligned elongated particles from theconduit toward the biological tissue.
 20. The method of claim 19,wherein the pre or post treating comprises at least one of a lasertreatment, a magnetic treatment, an electromagnetic treatment, anultrasonic treatment and a chemical treatment.